The Fractional exhaled Nitric Oxide (FeNO)- test as add-on test in the diagnostic work-up of asthma:a study protocol

Background: Asthma is a common disease characterized by chronic inflammation of the lower airways, bronchial hyperactivity, and (reversible) airway obstruction. The Global Initiative of Asthma Guideline recommends a flowchart to diagnose asthma with first-step spirometry with reversibility and a bronchial challenge test (BPT) with histamine or methacholine as a second step [1]. The BPT is considered burdensome, time-consuming for patients and staff, can cause side effects, and is expensive. In addition, this test strongly encumbers lung function capacity. Elevated Nitric Oxide (NO) is associated with airway eosinophilic inflammation in asthma patients and can be measured in exhaled air with the Fractional exhaled (Fe) NO-test. This low-burden FeNO-test could be used as an ‘add-on’ test in asthma diagnostics [2, 3]. Methods and analysis: This multi-center prospective study (Trial number: NCT06230458) compares the ‘standard asthma diagnostic work-up’ (spirometry with reversibility and BPT) to the ‘new asthma diagnostics work-up’ (FeNO-test as an intermediate step between the spirometry with reversibility and the BPT), intending to determine the impact of the FeNO-based strategy, in terms of the number of avoided BPTs, cost-effectiveness and reduced burden to the patient and health care. The cost reduction of incorporating the FeNO-test in the new diagnostic algorithm will be established by the number of theoretically avoided BPT. The decrease in burden will be studied by calculating differences in the Visual Analogue Scale (VAS) -score and Asthma Quality of Life Questionnaire (AQLQ) -score after the BPT and FeNO-test with an independent T-test. The accuracy of the FeNO-test will be calculated by comparing the FeNO-test outcomes to the (gold standard) BPTs outcomes in terms of sensitivity and specificity. The intention is to include 171 patients. Ethics and dissemination: The local medical ethics committee approved the proposed study and is considered a low-burden and risk-low study. The local medical ethics committee registration number: R23.005. Strengths and limitations of this study: Strengths: This is the first study that investigates the value of the FeNO-test (cut off ≥ 50 ppb) as an add-on test, to determine the impact of the FeNO-based strategy, in terms of the number of avoided BPTs, cost-effectiveness, and reduced burden on the patient and health care. Limitations: High FeNO levels may also be observed in other diseases such as eosinophilic chronic bronchitis and allergic rhinitis. The FeNO-test can be used to rule in a diagnosis of asthma with confidence, however, due to the poor sensitivity it is not suitable to rule out asthma.</p

The Fractional exhaled Nitric Oxide (FeNO)- test as add-on test in the diagnostic work-up of asthma:a study protocol

Background: Asthma is a common disease characterized by chronic inflammation of the lower airways, bronchial hyperactivity, and (reversible) airway obstruction. The Global Initiative of Asthma Guideline recommends a flowchart to diagnose asthma with first-step spirometry with reversibility and a bronchial challenge test (BPT) with histamine or methacholine as a second step [1]. The BPT is considered burdensome, time-consuming for patients and staff, can cause side effects, and is expensive. In addition, this test strongly encumbers lung function capacity. Elevated Nitric Oxide (NO) is associated with airway eosinophilic inflammation in asthma patients and can be measured in exhaled air with the Fractional exhaled (Fe) NO-test. This low-burden FeNO-test could be used as an ‘add-on’ test in asthma diagnostics [2, 3]. Methods and analysis: This multi-center prospective study (Trial number: NCT06230458) compares the ‘standard asthma diagnostic work-up’ (spirometry with reversibility and BPT) to the ‘new asthma diagnostics work-up’ (FeNO-test as an intermediate step between the spirometry with reversibility and the BPT), intending to determine the impact of the FeNO-based strategy, in terms of the number of avoided BPTs, cost-effectiveness and reduced burden to the patient and health care. The cost reduction of incorporating the FeNO-test in the new diagnostic algorithm will be established by the number of theoretically avoided BPT. The decrease in burden will be studied by calculating differences in the Visual Analogue Scale (VAS) -score and Asthma Quality of Life Questionnaire (AQLQ) -score after the BPT and FeNO-test with an independent T-test. The accuracy of the FeNO-test will be calculated by comparing the FeNO-test outcomes to the (gold standard) BPTs outcomes in terms of sensitivity and specificity. The intention is to include 171 patients. Ethics and dissemination: The local medical ethics committee approved the proposed study and is considered a low-burden and risk-low study. The local medical ethics committee registration number: R23.005. Strengths and limitations of this study: Strengths: This is the first study that investigates the value of the FeNO-test (cut off ≥ 50 ppb) as an add-on test, to determine the impact of the FeNO-based strategy, in terms of the number of avoided BPTs, cost-effectiveness, and reduced burden on the patient and health care. Limitations: High FeNO levels may also be observed in other diseases such as eosinophilic chronic bronchitis and allergic rhinitis. The FeNO-test can be used to rule in a diagnosis of asthma with confidence, however, due to the poor sensitivity it is not suitable to rule out asthma.</p

The use of a direct bronchial challenge test in primary care to diagnose asthma

Many asthmatics in primary care have mild symptoms and lack airflow obstruction. If variable expiratory airflow limitation cannot be determined by spirometry or peak expiratory flow, despite a history of respiratory symptoms, a positive bronchial challenge test (BCT) can confirm the diagnosis of asthma. However, BCT is traditionally performed in secondary care. In this observational real-life study, we retrospectively analyze 5-year data of a primary care diagnostic center carrying out BCT by histamine provocation. In total, 998 primary care patients aged ≥16 years underwent BCT, without any adverse events reported. To explore diagnostic accuracy, we examine 584 patients with a high pretest probability of asthma. Fifty-seven percent of these patients have a positive BCT result and can be accurately diagnosed with asthma. Our real-life data show BCT is safe and feasible in a suitably equipped primary care diagnostic center. Furthermore, it could potentially reduce diagnostic referrals to secondary care

Mepolizumab add-on therapy in a real world cohort of patients with severe eosinophilic asthma: response rate, effectiveness, and safety

Introduction: Severe eosinophilic asthma is an incapacitating disease. Mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, proved to be effective as an add-on therapy in patients with severe eosinophilic asthma. However, only data from randomized controlled trials are available and real world data are lacking. Methods: A retrospective observational longitudinal study was conducted in a real world cohort of patients with severe eosinophilic asthma treated with mepolizumab. The primary objective was to determine response rate, based on a global evaluation of treatment effectiveness by the treating pulmonologist. Secondary objectives were to assess exacerbation frequency, systemic maintenance glucocorticoid usage, Asthma Control Questionnaire (ACQ), lung function, and adverse events. Results: Seventy-eight patients were included. Treatment with mepolizumab was considered beneficial and was therefore continued in 75.6% of patients 12 months from the initiation of mepolizumab. The most common reason for drop-out was insufficient response. Secondary objectives: 12 months from the initiation of mepolizumab there was a decrease of 3.2 (CI 2.5–4.1; p < 0.001) severe asthma exacerbations per year, a decrease of ACQ of 0.80 points (CI 0.49–1.12; p < 0.001), and an increase of 3.7 (CI 0.3–7.2; p = 0.034) percent of predicted FEV1 compared to baseline. At baseline 51.3% of patients were treated with systemic glucocorticoid maintenance therapy, compared to 15.4% (p < 0.001) of patients 12 months from the initiation of mepolizumab. No serious adverse events considered to be related to mepolizumab were reported. Conclusion: This study confirms that mepolizumab add-on therapy is effective and safe in a real world cohort of patients with severe eosinophilic asthma

The development and validation of a novel, parameter-free, modelling strategy for electromembrane processes: Electrodialysis

As the global water crisis worsens and natural resources of strategic inorganic elements dwindle, the need for efficient and effective salt separation methods is becoming ever more important. Electromembrane processes, and in particular electrodialysis, are emerging as efficient and effective separation technologies that use an electric field to drive the transport of ions against a concentration gradient. Modelling electromembrane processes allows for process design and optimisation, as well as the identification of what technological improvements would have the greatest effect. However, the wide use of empirical fitting parameters in most existing models greatly limits their globality. The presence of complex and confounding phenomena within electromembrane processes greatly exacerbates this. In this work, a novel, circuit-based modelling strategy for electromembrane processes is presented, avoiding the use of any fitting parameters. Conventional electrodialysis is adopted as a case study. The implementation of a novel transport number model and membrane resistance model are crucial for model accuracy over a wide range of process conditions. The model was experimentally validated and showed excellent agreement with experimental data across a range of concentrations and voltages. Consequently, this model will prove to be an excellent tool for researchers and process designers

Differentiating interstitial lung diseases from other respiratory diseases using electronic nose technology

Introduction: Interstitial lung disease (ILD) may be difficult to distinguish from other respiratory diseases due to overlapping clinical presentation. Recognition of ILD is often late, causing delay which has been associated with worse clinical outcome. Electronic nose (eNose) sensor technology profiles volatile organic compounds in exhaled breath and has potential to detect ILD non-invasively. We assessed the accuracy of differentiating breath profiles of patients with ILD from patients with asthma, chronic obstructive pulmonary disease (COPD), and lung cancer using eNose technology. Methods: Patients with ILD, asthma, COPD, and lung cancer, regardless of stage or treatment, were included in a cross-sectional study in two hospitals. Exhaled breath was analysed using an eNose (SpiroNose) and clinical data were collected. Datasets were split in training and test sets for independent validation of the model. Data were analyzed with partial least squares discriminant and receiver operating characteristic analyses. Results: 161 patients with ILD and 161 patients with asthma (n = 65), COPD (n = 50) or lung cancer (n = 46) were included. Breath profiles of patients with ILD differed from all other diseases with an area under the curve (AUC) of 0.99 (95% CI 0.97–1.00) in the test set. Moreover, breath profiles of patients with ILD could be accurately distinguished from the individual diseases with an AUC of 1.00 (95% CI 1.00–1.00) for asthma, AUC of 0.96 (95% CI 0.90–1.00) for COPD, and AUC of 0.98 (95% CI 0.94–1.00) for lung cancer in test sets. Results were similar after excluding patients who never smoked. Conclusions: Exhaled breath of patients with ILD can be distinguished accurately from patients with other respiratory diseases using eNose technology. eNose has high potential as an easily accessible point-of-care medical test for identification of ILD amongst patients with respiratory symptoms, and could possibly facilitate earlier referral and diagnosis of patients suspected of ILD.</p

Development of an integral assessment approach of health status in patients with obstructive airway diseases: the CORONA study

Traditional assessment of patients with obstructive lung diseases (asthma and chronic obstructive pulmonary disease; COPD) relies on physiological tests. The COPD and Asthma Rotterdam Integrated Care Approach (CORONA) study aims to develop a diagnostic pathway with a more comprehensive approach to the assessment of patients with asthma and COPD in secondary care. Methods: An eight-step method was used to develop and implement the pathway for patients with asthma or COPD referred to an outpatient hospital setting. Results: The diagnostic pathway consists of an evidence-based set of measurements prioritized by a Delphi procedure. The pathway incorporates three innovative diagnostics: the metronome-paced hyperventilation test to measure dynamic hyperinflation, an activity monitor to objectively evaluate physical activity in daily life, and the Nijmegen Clinical Screening Instrument as a comprehensive assessment tool to acquire detailed insight into symptoms, functional limitations, and quality of life. Conclusion: An innovative diagnostic pathway was developed and implemented for patients with obstructive lung diseases referred to secondary care. As this pathway aims to provide a comprehensive analysis of health status, it focuses on biomedical aspects and also reviews behavioral aspects that further elucidate the patient’s health status. The added value of the diagnostic pathway needs to be determined from both an organizational perspective and from the individual patient’s viewpoint

Implementing integrated care guidelines in asthma and COPD:It ain’t easy!

Objective: To evaluate the implementation of a guideline-based, integrated, standardised, personal approach in patients with Chronic ObstructivePulmonary Disease (COPD) or Asthma in a real-life situation.Methods: Patients at the outpatient clinic of the department of pulmonary disease were included in a controlled cohort study, comparing the use ofdiagnostic items and ‘Personalised care plans’ (PCPs) in patients with obstructive lung disease before (2013) and after (2015) implementation of apersonalised diagnostic pathway. Results were compared with reference data (2016) from two control hospitals that used the same guidelines butdid not implement this pathway.Results: 100 patients were selected for all three cohorts. After implementing the diagnostic pathway in 2015, 35 % of patients visited attended allpre-planned appointments, whereas 65 % of patients did not: they were diagnosed using usual care. Factors contributing to patients not attendingthe diagnostic care pathway were: the logistical complexity and intensity of the 2-day pathway, patients willingness to participate in a personalisedpathway, and low social economic status or low literacy. After the implementation of the pathway, a significant improvement was seen in thenumber of PCPs (P &lt; 0.001) and the number of diagnostic items registered recorded in the patients’ electronic medical records (P &lt; 0.001).Conclusion: Implementing a standardised diagnostic pathway in a real-life population significantly improved the number of personalised care plans,demonstrating that the implementation of holistic care planning is feasible in this population. Nevertheless, the pathway needs further improvements to maximize the number of patients benefitting from it, including logistical streamlining, removing unnecessary diagnostic tools, andincreasing the focus on low literacy. Additionally, we found that implementing existing guidelines in a real life context is complex. Therefore, it isrequired to prioritize the translation of current guidelines into every-day practice, before expanding existing guidelines and protocol

The development and evaluation of a parameter-free circuit-based model of bipolar membrane electrodialysis for process design and optimisation

Bipolar membrane electrodialysis (BPMED) is an emerging electromembrane technology which has the potential to replace existing pH manipulation process units among others and take advantage of the benefits posed by process electrification. The development of robust and flexible process models of BPMED for design and optimisation is paramount in derisking potential instillations and improving commercial viability. Herein, a circuit-based model of BPMED is presented which avoids reliance on empirical fitting parameters and training data. The resulting model is flexible enough that extension to account for added complexities may be readily adopted. The mass transfer and electrical resistance of six different domains (three membranes and three streams) were computed by applying fundamental laws such as Ohm’s law and Faraday’s first law. Acid-base reactions and their effect releasing current within the membranes were also considered. Furthermore, the stack model can be readily embedded in a broader process model. To this end, the stack model is applied to a recirculating-batch experiment using a delayed differential material balance to account for dead-time within the tubing and measurement flow-cells. Two orthogonal methods of experimental validation were conducted to assess the performance of the model over a range of concentrations and applied voltages. These involved running a recirculating-batch experiment and collecting current–voltage polarisation data, respectively, and both showed good agreement with the model predictions. Overall, a robust model of BPMED has been produced which is able to accurately predict system performance and will prove useful for the design and optimisation of industrial systems